The minimally conscious state (MCS) describes a low level of functional recovery of cognition following a severe brain injury. Unlike patients in the vegetative state, MCS patients respond to their environment, may show relatively complex responses to verbal commands, and produce limited verbal expressions. Significant functional recoveries at long intervals can be observed in MCS patients (e.g., recovery of speech after years). The present proposal seeks to improve understanding of the neurophysiological mechanisms underlying MCS and to develop diagnostic evaluations to identify potential cognitive reserve in patients with severe brain injuries. Preliminary data obtained from multimodal neuroimaging studies of MCS patients supports a working hypothesis that the MCS brain is chronically underactive, yet may retain dormant large-scale integrative cerebral networks. We plan to carefully and longitudinally characterize brain function in patients who have stabilized at a functional level meeting the accepted criteria for MCS using quantitative electroencephalography (EEG), fluorodeoxyglucose-positron emission tomography (FDG-PET), diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI). Preliminary studies support combining these measures to test the hypothesis that MCS patients recover integrative brain function but, due to low resting neuronal activity resulting from dynamic abnormalities in the thalamocortical system, remain unable to consistently form and maintain dynamical brain activity underlying communication and goal-directed behavior. We will test the additional hypothesis that slow structural remodification of the brain generally arise after severe traumatic brain injury. Approximately 100,000 Americans each year incur long-term substantial loss of function from severe traumatic brain injuries. The immediate goal of the proposed studies is to provide a foundation for developing methods to study the natural history of evolution of recovery of cognitive function following severe brain injury. The long-range goal of the studies proposed here is to build a set of quantitative indices to help identify MCS patients with recruitable neuronal populations who may be candidates for emerging trials of palliative interventions aimed at improving communication. The patient population under study is large, poorly characterized, and vastly underserved;moreover, they are uniquely vulnerable to misdiagnosis and neglect. These neuroimaging studies will help identify patients who have been mistaken as permanently unconscious but may have the capacity to recover communication. Without such studies, these patients will continue to remain categorically excluded from advances in medical diagnostics and therapeutics.